Results seen as supporting statins' overall safety in youth with familial hypercholesterolemia.

Action Points

Familial hypercholesterolemia is associated with a reduced prevalence of type 2 diabetes.

The prevalence of type 2 diabetes in familial hypercholesterolemia varies according to the specific genetic mutation causing the elevated cholesterol.

Statin users have a modestly elevated risk for developing type 2 diabetes, but the reason for this has not been known. Now a study showing a lower prevalence of diabetes in people with inherited high cholesterol may help explain the link.

In the cross-sectional analysis from the Netherlands, patients with familial hypercholesterolemia were found to have a 51% lower odds of having type 2 diabetes compared with relatives without the cholesterol disorder, and diabetes prevalence varied by gene mutation type.

The findings suggest that cellular cholesterol uptake, which is the common pathway in familial hypercholesterolemia, plays an important role in the development of type 2 diabetes. It may also have implications for diabetes treatment, researcher Kees Hovingh, MD, PhD, of the University of Amsterdam's Academic Medical Center in the Netherlands, and colleagues wrote in the March 10 issue of the Journal of the American Medical Association.

"If these findings are confirmed in longitudinal studies, they might provide support for development of new approaches to the prevention and treatment of type 2 diabetes by improving function and survival of pancreatic beta cells," they wrote.

One in every 250 to 300 people have the cholesterol disorder, which is associated with a greatly elevated lifetime risk for cardiovascular disease.

Preiss, who is a senior lecturer in cardiology at the University of Glasgow, Glasgow, Scotland, said the findings suggest that the strategy of starting statin therapy very early in life in people with high cholesterol genetic disorders is both safe and warranted.

"There has been concern that starting statins in childhood or in the teen years would potentially increase diabetes risk," Preiss told MedPage Today. "What this study tells us is that even if statins modestly increase diabetes risk, we really don't need to worry because these people are starting from such a low baseline risk."

LDL-Elevating Mutations Lower Diabetes Risk

The newly published research confirms anecdotal reports suggesting that people with familial hypercholesterolemia have a lower risk for type 2 diabetes than the general population.

Hovingh and colleagues hypothesized that this reduced risk occurs because pancreatic beta cells in people with the condition have decreased cholesterol uptake and improved function and survival.

Using the largest database of patients with familial hypercholesterolemia in the world, the researchers tested this hypothesis. They were also able to examine the dose-response relationship between decreased cholesterol uptake and type 2 diabetes.

The cross-sectional study included people screened for familial hypercholesterolemia mutations between 1994 and 2014, and the final analysis included more than 60,000 patients with the mutations and unaffected family members.

Familial hypercholesterolemia most often involves mutations in the LDL receptor (LDLR) gene, but apolipoprotein B (APOB) gene and proprotein convertase subtilisin/kexin type 9 (PCSK9) mutations can also cause the condition.

Among those with familial hypercholesterolemia included in the analysis, 86% had LDLR mutations, 13.8% had APOB mutations, and 0.2% had PCSK9 mutations.

Potential limitations cited by the researchers included the study's cross-sectional design, the fact that study participants self-reported their diabetes, the potential for survival bias, and the potential for unmeasured confounders.

But in an editorial published with the study, Preiss and Naveed Sattar, MD, PhD, wrote that "no better study currently exists to address this question" due to the large cohort of carefully screened participants.

"The study ... contributes important evidence to strengthen the previous observed relationship between statin therapy and diabetes risk," they wrote. "However, this does not and should not alter guidance regarding the use of these important medications in patients at elevated cardiovascular risk given the clear overall benefit of statin therapy."

Preiss said statin users concerned about diabetes risk can mitigate the increased risk by making lifestyle changes, such as losing weight if they are overweight or obese, or exercising.

"This is a potential side effect (statin users) should be told about, but if a patient warrants statin therapy, there is no question in my view that the benefits of taking a statin outweigh the risks," he said.

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